OP0165 JAK3-STAT5 SIGNALING PATHWAY IS INVOLVED IN THE PATHOGENESIS OF GOUTY INFLAMMATION
Authors: F. N. Xiao, G. L. Jian, Q. B. Zhang, Y. Xie, T. Li, Z. M. Xu, Y. F. Qing
Journal: Annals of the Rheumatic Diseases (2022)

Background Studies have confirmed that JAKs-STATs signaling pathway is involved in the pathogenesis of a variety of autoinflammatory diseases, and has been transformed into the treatment of rheumatic diseases. So far, the research of JAKs-STATs in the mechanism of gout is very limited. Objectives To determine whether JAKs-STATs pathway is involved in the pathogenesis of gouty inflammation. Methods 1.The transcription and protein phosphorylation levels of 4 JAKs (JAK1, JAK2, JAK3 and Tyk2) and 7 STATs (STAT1, stat2, STAT3, STAT4, STAT5a/5b and STAT6) in PBMCs of 100 gout patients (concluding acute gout (AG) and intermittent gout (IG) patients 50 cases, respectively) and 50 healthy subjects (HC) were measured; 2.To detect the changes of JAK3-STAT5 signal pathway in synovium of rat ankle model of gouty inflammation;3.To explore the changes of JAK3-STAT5 signal pathway in synovium of gouty inflammation model after colchicine treatment. Results 1.The phosphorylation levels of JAK3 and STAT5 in PBMCs,the plasma IL-2 level in the AG group were all significantly higher than those in the HC group (P&lt;0.05, respectively; Figure 1G,H), while there were no differences with respect to the other JAKs and STATs molecules between the two groups (P&gt;0.05, respectively); 2.JAK3 and STAT5 phosphorylation levels in synovial tissue of rat ankle, cytokine IL-1β and IL-2 productions in synovial fluid of rat ankle from gout model were all significantly increased (P&lt;0.05, respectively;Figure 1A-F);3.Phosphorylation levels of JAK3 and STAT5,IL-1β and IL-2 levels were significantly reduced after colchicine treatment (P&lt;0.05, respectively;Figure 1A-F) Figure 1. JAK3-STAT5 participates in the pathogenesis of gouty inflammation . In vivo experimental protocol (A-F): A. Male Wistar rats were used. The model Colchicine group was intragastrically administered with 0.104 mg/kg/d colchicine solution, and the Control group was intragastrically administered with the same amount of saline. After 3 days of continuous intragastric administration, the right ankle joint was injected with MSU (8 mg/100μl) or PBS (100 μl) to establish a gout arthritis model(MSU group) or Control group. B. Representative photographs of ankles 12 hr after MSU or PBS injection. C. Representative microscopic photos of ankle tissue sections from Control, MSU and Colchicine groups. D. Representative confocal laser scanning images showed JAK3 protein and its phosphorylated protein staining in ankle tissues in the three groups. Areas staining positive for JAK3 protein are shown in green. Regions staining positive for p-JAK3 protein are shown in red. E. IL-1β and IL-2 production in ankle flushing was detected by ELISA.*P &lt;.05,**P&lt;.01,***P&lt;.001, significantly different from Control group; #P&lt;.05,##P&lt;.01, ###P&lt; .001,significantly different from MSU group. F. At 12 h after MSU injection, JAK3 and STAT5 mRNA, protein in ankle tissues were determined by qRT-PCR and Western blotting, respectively. The panel displays the representative images of JAK3, STAT5, p-JAK3, p-STAT5a and GAPDH protein expression from the three groups.*P &lt;.05,**P&lt;.01,***P&lt;.001, significantly different from Control group; #P&lt;.05,##P&lt;.01, ###P&lt; .001, significantly different from MSU group. G.IL-2 and IL-7 levels in plasma of acute gout(AG), intermittent gout(IG) patients and healthy individuals (HC) were detected using ELISA. *P&lt;.05, **P&lt;.01, ***P &lt; .001. H. JAK3 and STAT5 mRNA, protein levels in PBMCs of AG, IG, and HC groups were measured by qRT-PCR and Western blotting, respectively. *P&lt;.05, **P&lt;.01, ***P &lt; .001. Conclusion IL-2-JAK3-STAT5 signaling pathway is involved in the regulation of gouty inflammation. Colchicine could treat gouty inflammation through inhibiting IL-2-JAK3-STAT5 pathway; JAK3 is expected to be a therapeutic target for acute gouty inflammation. Disclosure of Interests None declared